ABSTRACT Systemic lupus erythematosus (SLE or lupus) is a prototype of type-I interferon (IFN-I)-mediated autoimmune disease, characterized by a myriad of clinical manifestations including inflammation, pathogenic autoantibody production, and irreversible end-organ damage (e.g. kidneys). SLE disproportionately afflicts women (nine-fold higher than men) and non-white ethnicities. Asians and African-Americans have higher SLE incidence, more severe disease manifestations, and greater risk of organ damage (e.g. lupus nephritis) than Caucasians. Others and we have reported that several IFN regulatory genes, including IFN regulatory factor 8 (IRF8), and solute carrier family 15 number 4 (SLC15A4) are involved in SLE susceptibility. IFNs are a family of cytokines with important roles in infection, cancer, and autoimmunity. In vitro evidence suggests that plasmacytoid dendritic cells (pDCs), the principal IFN-I producing immune cells, are intimately involved in SLE development. A recent study using two mouse models (Irf8-/- knockout and Slc15a4 mutant) provided direct evidence that pDCs contribute to SLE via hyper-production of IFN-I. Thus, IRF8 and SLC15A4 could potentially be involved in human SLE progression. Our genetic association data identified several potential SLE predisposing variants for IRF8 (best p=1.2x10-22) and for SLC15A4 (best p=1.5x10-21) across multiple ethnicities. However, despite strong association, specific pathogenic variants and their underlying molecular mechanisms are not yet defined. Using bioinformatics, we predicted that several associated variants are cis-eQTLs, with roles in regulating gene expression. Using luciferase and ChIP-qPCR, we experimentally validated allele-specific effects of several predicted functional variants. Since IFN gene signatures are a prominent feature in SLE, we hypothesize that comprehensive, trans-ethnic mapping (TEM) followed by experimental validation with functional genetics, including genetic and epigenetic editing in relevant immune cells, will identify causal variants and their functional consequences in IFN-I production. Our research team has the expertise, resources, and track records to discover and characterize functional variants for SLE. In Aim 1, we will localize SLE-predisposing variants from these genes by performing comprehensive imputation-based TEM across ethnically diverse populations (N>30,000 from Asians, African-Americans, European-Americans, Egyptians, and Hispanics). Promising variants, especially imputed and low-frequency variants, will be validated through additional confirmatory genotyping. We will elucidate genetic and clinical heterogeneity by assessing associations with clinical sub-phenotypes and autoantibodies. In Aim 2, we will experimentally validate functional relevance of putative variants as regulators of gene expression and IFN-I production. We will use both cultured cells (THP-1) and primary immune cells (pDCs, monocytes) from SLE patients and controls. Insights gained from this project will help to define the molecular mechanisms underlying how risk alleles predispose to SLE, and may define novel drug/therapeutic targets for SLE in the future.